This projects delineates biochemical and pharmacological properties of sigma receptors and ligands. In this fiscal year, we found that a neuroleptic sulpiride can potentiate the NMDA-induced increase in intracellular calcium concentration and that this action of sulpiride is in turn enhanced by sigma ligands. Also, it was found that this action of sulpiride is blocked by protein kinase A inhibitor. The results indicate a relationship between the action of neuroleptics and sigma ligands and suggest that the action of either or both classes of drugs could invlove intracellular calcium signaling and protein hosphorylation. Behaviorally, we found that a synthetic sigma ligand PRE-084, like neurosteroids pregnenolone sulfate and dihydroepiandrosterone, improves learning and memory in mice whose mnemonic capacities were compromized by the icv injection of beta-amyloid peptide 25-35. Further, the action of all three compounds are blocked by progesterone, a neurosteroid which binds sigma receptors. Thus, sigma receptor ligands may represent a new class of compounds for developing antiamnesic agents.